Introduction

The impairment of the sense of smell impacts about one quarter of adults older than age 50 in the US, increasing to nearly two-thirds of those over 80 years. Of public health importance, researchers have found a racial difference between blacks and whites in the United States, with black adults having a higher prevalence of smell dysfunction.

Chronic diseases, including Alzheimer’s disease and Parkinsonism, can present with the loss of smell. However, the most common cause of smell impairment follows a viral syndrome, known as post-viral anosmia, and comprises approximately 20-30 percent of cases.

When COVID-19 was declared a pandemic in March of 2020, we began to learn of a common, early complaint of COVID-19: the sudden loss of smell or anosmia. In fact, it is regarded as an indicator of COVID-19, including in those with mild disease.

Studies suggest that as many as 10% of those infected with SARS-CoV-2 develop loss of smell that does not return after 6 months. This long-term condition could involve as many as 150,000 Americans over the next year. Up to now, the loss of smell was considered a minor issue after viral infections, but some people with COVID-19 report a delay in return to normal even after a year.

A Brief Overview of Smell

Post-Viral Smell Loss and COVID

The loss of smell after a viral infection, or post-viral anosmia, accounts for 20-30% of causes of loss of taste and smell (1). Often this comes with a loss or perversion of taste, known as ageusia or dysgeusia, respectively. The mechanisms of anosmia are not entirely known. At least some of it may be related to nasal swelling and obstruction from localized infection. There is also a component of indirect and direct sensorineural damage caused by the infection.

Post-viral anosmia appears to be more common after COVID-19 than other respiratory viral infections. In a group of 202 mildly symptomatic outpatients with anosmia, two-thirds (130 ) reported some degree of altered taste or smell (2). A one-month survey of the same group after this study indicated that nearly half (48.7%) had a complete return of smell and taste after four weeks, while 40% had some improvement. The remaining 10% of this group had unchanged or worsened symptoms after COVID-19 (3).

Interestingly, COVID-19 anosmia may even be a predictor of less severe disease.

COVID and the Olfactory Bulb

Case Example of Anosmia

Case: A 30 year-old was bitten by a mulga snake (Pseudechis australis). The ER concluded that it was a mild envenomation. Over the ensuing weeks, he developed the complete loss of smell. An MRI showed reduced volume of the both olfactory bulbs, corresponding to the anosmia.

The case above illustrates that even a process distant to the nose can lead to anosmia, presumably from a direct or indirect effect (e.g. inflammatory mediators) of the venom.

In viral infections, the exact mechanisms of how loss of smell develops are not completely known. Conceivably, after someone develops an infectious or inflammatory condition, local and systemic inflammation can occur that damage the olfactory bulb. Interestingly, the olfactory bulb is a hub of the innate and acquired immune system.

Possible Cause of Post-Viral Anosmia

Researchers have long postulated that a viral infection may gain entry to the brain from the nasal tissue via infection of the olfactory bulb(4). The olfactory neurons coalesce after traversing through the cribriform plate of the ethmoid bone to form the olfactory bulb within the brain. A series of studies in viruses such as influenza, herpes simplex, and varicella zoster support that infection of the neurons is likely the mechanism in which viruses gain access to the central nervous system.

Post-COVID Anosmia

Given the common finding of anosmia, some researchers have speculated whether SARS-CoV-2 infects olfactory neurons. However, scientists identified the ACE2 receptors in epithelial cells of the nasal membrane. If you recall, ACE2 is the cell receptor protein that SARS-CoV-2 uses to enter and infect cells. A SARS-CoV-2 animal model suggested that, rather than direct infection of the olfactory sensory neurons, SARS-CoV-2 infects supporting epithelial cells known as sustentacular cells and leads to massive damage of this tissue (5).

Studies and case reports seem to contradict the absence of neuronal infection. An MRI of a patient with anosmia for two months after COVID showed decreased olfactory bulb volume without nasal congestion or obstruction. Pathology reports of two patients who died from SARS-CoV-2 showed changes consistent with dying, inflamed tissue (“necrotizing olfactory bulbitis”) (6) Other MRI studies have shown inflammation of the olfactory bulb with “edema” more than 3 weeks after infection. All of these findings suggest that COVID-19 results in neuronal inflammation.

The findings suggest that inflammation induced by COVID-19, and in some cases direct infection, leads to damage of the olfactory bulb (7). Given necrotizing changes found on histology in COVID-19 infections, those with persistent anosmia after several months are likely not to wholly recover their lost sense of smell. Xydakis et al. suggest observing a patient for 12-24 months before designating the olfactory impairment as “permanent.”

Treatment of Loss of Smell after COVID

Do Nasal Steroids Work?

Since there is some inflammation of the nasal epithelial cells and steroids are effective in severe COVID-19, could a nasal steroid provide additional benefit in patients with anosmia?

A randomized, controlled trial of a nasal steroid (mometasone furoate) in 50 patients with post-COVID-19 anosmia did not show any improvement of smell scores after three weeks over to the control group (8).

Does smell training therapy work?

It is likely that retraining the brain to sense smells may come with some success, but the degree of benefit for COVID-19 is still unclear.

In smell therapy, a person smells essential oils like rose, lemon, lavender, and eucalyptus for 30 seconds a few times a day. A study of Coronavirus Smell Therapy for Anomia Recovery (Co-STAR) is currently enrolling patients with anosmia to develop and the test the benefit of this type of therapy.

Conclusion

1. Post-viral anosmia is common with COVID-19 with as many as 60% developing the process. It typically improves gradually over the course of a few months in the majority. However, as many as 10% will have long-term impairments of smell.
2. The mechanism of anosmia appears to relate to local infection of nasal epithelial cells with SARS-CoV-2. Either from infection or inflammatory changes, the optic neurons and bulb become inflamed, injured, and die.
3. Smell therapy appears to be a promising option, although trials are underway to determine how effective it is.

References

1. Seiden A. Postviral olfactory loss. Otolaryngol Clin North Am. 2004; 37(6):1159-66. doi: 10.1016/j.otc.2004.06.007.
2. Spinato G, Fabbris C, Polesel J. Alterations in Smell or Taste in Mildly Symptomatic Outpatients with SARS-CoV-2 Infection. JAMA. 2020; 323(20):2089-2090. doi:10.1001/jama.2020.6771. Accessed 8/25/2021.
3. Boscolo-Rizzo P, Borsetto D, Fabbris, et al. Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19. JAMA Otolaryngol Head Neck Surg. 2020; 146(8):729-732.
4. Van Riel D, et al. The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. J Pathol. 2015. 235(2):277-87. doi:10.1002/path.4461.
5. Bryche B, et al. Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters. Brain Behav Immun. 2020; 89:579-586. doi:10.1016/j.bbi.2020.06.032. Accessed 8/25/2021.
6. Stoyanov G, et al. Gross and Histopathology of COVID-19 With First Histology Report of Olfactory Bulb Changes. Cureus. 2020; 12(12):e11912. doi:10.7759/cureus.11912.
7. Xydakis M, et al. Post-viral effects of COVID-19 in the olfactory system and their implications. 2021 Sep: 20(9):753-761. doi: 10.1016/S1474-4422(21)00182-4.
8. Abdelalim A, et al. Corticosteroid nasal spray for recovery of smell sensation in COVID-19 patients: A randomized controlled trial. Am J Otolaryngol. Mar-Apr 2021; 42(2):102884. doi: 10.1016/j.amjoto.2020.102884.